- Title
- Impact of neonatal infection on adult hippocampal glucocorticoid and mineralocorticoid receptors and hypothalamic-pituitary-adrenal axis outcomes
- Creator
- Wynne, Olivia
- Relation
- University of Newcastle Research Higher Degree Thesis
- Resource Type
- thesis
- Date
- 2010
- Description
- Research Doctorate - Doctor of Philosophy (PhD)
- Description
- The impact of early life insults on adult physiology is well established with respect to early life stressors such as maternal psychological stress, neonatal separation, maternal under-nutrition and perinatal exposure to excess glucocorticoids resulting in maladaptive programming. Newborns are particularly susceptible to bacterial and fungal infections as the immune system of the neonate in both humans and animal models is underdeveloped at birth. The components of the stress response are vulnerable such programming. It has been found, in this laboratory and others, that perinatal exposure to models of infection such as lipopolysaccharide (LPS) in the rat result in a number of maladaptive programming outcomes such as attenuated corticosterone response to stress, decreased resistance to tumour immunity in adulthood, altered circulating levels of corticosterone, in addition to blunting and extending corticosterone response to stress. However, there are limited data on the effects of perinatal infection on adult outcomes in the mouse, with no studies examining the effects of perinatal infection with live bacteria on HPA axis outcomes. The experiments outlined in this thesis were designed to find evidence of such programming in the mouse model due to neonatal infection with live bacteria. The experiments in the pilot study (chapter four) first sought to establish evidence of programming in the mouse model by using qRT-PCR on mRNA taken from the whole brain of mice neonatally infected with Chlamydia. muridarum and compare mRNA abundance to sham-infected controls. As detailed in the chapter, evidence of programming was been established, with significant decreases in mineralocorticoid receptor (MR) and corticotrophin releasing hormone (CRH) mRNA in the males after neonatal infection to C. muridarum. Also, there was evidence of sexually differentiated receptor expression with males in the control condition having significantly more CRH mRNA than the females in the same condition. The study confirmed the mouse is a suitable model to examine the role of neonatal infection in programming alterations to the adult stress response, justifying more in-depth investigation of the model. The second study (chapter five) demonstrates for the first time that neonatal bacterial infection leads to alterations in the hippocampus in the adult and there are considerable sex differences in the hippocampal phenotypes that emerge in adulthood after perinatal stress. In male adults exposed to infection at birth, hippocampal glucocorticoid receptor (GR) and MR mRNA abundance were reduced and the circulating corticosterone levels increased when compared to their same sex controls, while GR protein was reduced and MR protein increased. The female adults exposed to infection had increased GR and MR mRNA and decreased circulating corticosterone. This study found that neonatal respiratory infection significantly impacts adult hippocampal GR and MR, and circulating corticosterone in a sex specific manner potentially altering stress responsivity. After establishing the mouse and live infection as a viable model for investigating the impact of neonatal stress, we then aimed to investigate the outcomes of such infection on hippocampal whole genome expression. The data from the third study (chapter six) indicate that adult gene expression profiles were altered. Males exposed to infection early in life exhibited gene changes associated with tissue morphology or cellular development such as CDKN1A, a regulator of cell cycle progression, when compared to same sex controls. In contrast, females exposed to infection in early life exhibited a T-helper type 2 cytokine bias with an up-regulation of genes related to humoral immunity such as interleukin (IL)-6 and IL-10 when compared to females in the control condition. In the final study (chapter seven), the effects of re-infection on hippocampal corticosterone receptors and circulating corticosterone, adrenocorticotropic hormone, tyrosine hydroxylase (TH) protein and adrenal weight were measured. The results demonstrate that neonatal infection alters hippocampal corticosterone receptors, adrenal TH protein and circulating corticosterone. Significant differences due to sex and treatment were observed at the level of protein for the corticosterone receptors and TH suggesting effects of infection manifest at the level of protein. No difference was observed due to sex for MR mRNA and circulating corticosterone, suggesting that these factors may not be sex specifically regulated. Taken together, the data presented in this thesis demonstrate for the first time that neonatal bacterial infection leads to alterations in the hippocampus in the adult mouse and that there are sex differences in the hippocampal phenotypes that emerge in adulthood after perinatal stress. The sex differences do not begin at adolescence, but are present in the neonate’s initial response to infection. This is the first time that infection with live bacteria has been used to show adult programming in the mouse model. This thesis has demonstrated that the mouse and live bacterial infection is a viable model with which to investigate neonatal programming effects on adult parameters. Furthermore, given the role of the hippocampus in the regulation of HPA function, these observations have implications for immune and endocrine function as well as stress responsivity.
- Subject
- neonatal infection; hippocampus; glucocorticoids; immune system; perinatal infection; adult gene expression
- Identifier
- http://hdl.handle.net/1959.13/808705
- Identifier
- uon:7728
- Rights
- Copyright 2010 Olivia Wynne
- Language
- eng
- Full Text
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| Thumbnail | File | Description | Size | Format | |||
|---|---|---|---|---|---|---|---|
| View Details Download | ATTACHMENT01 | Abstract | 102 KB | Adobe Acrobat PDF | View Details Download | ||
| View Details Download | ATTACHMENT02 | Thesis | 5 MB | Adobe Acrobat PDF | View Details Download |